The overarching goal of this competitive renewal application is to examine the pleiotropic effects of arteriosclerosis (AS), on brain structure and function, either alone or in combination with Alzheimer disease (AD). We propose a prospective, longitudinal study of a convenience sample (231 current + 276 new = 507 subjects), selected using the Framingham cardiovascular risk profile (FCRP) to ensure representation of subjects ranging from little to severe arteriosclerosis (AS). The PPG includes 4 Cores (Administrative, Clinical, Imaging, and Pathology) and 4 Projects. Project 1 (Reed & Jagust) will use amyloid imaging (Pittsburgh Imaging B [PIB] compound) to identify in vivo a cohort of subjects representing the full spectrum of AS, with minimal AD pathology. Project 2 (Weiner, DeCarli, and Singh) will determine the extent to which arteriosclerosis (AS) is associated with changes of brain perfusion and volume and integrity of gray matter (GM) and white matter (WM) and the extent to which these associations relate to AD- vs. CVD-pathology. .Project 6 (Zarow & Vinters) seeks to improve the clinical diagnosis of hippocampal sclerosis and to clarify its pathogenesis. Project 7 (Chui & Mungas) will test the overarching hypothesis using data obtained in the Clinical, Imaging, and Pathology Cores.